This application represents a competitive renewal of my current Level II RSDA at a K05 RSA at a K05 RSA level, as recommended by NIMH program staff. The focus of my research program is on brain asymmetry related to emotion and affective disorders. The research utilizes quantitative electrophysiological (EEG) procedures and more recently positron emission tomograph (PET) in addition to behavioral and autonomic methods. We have proposed that the left prefrontal region plays an important role in approach-related behavior and emotion an that decreased activation in this region may result in increased vulnerability to depression, which is conceptualized as a disorder of approach. Anterior regions of the right hemisphere are hypothesized to be selectively activated during withdrawal- related emotion and activation in this region may be associated with certain forms of anxiety. Other structures are also hypothesized to play an important role in these circuits, particularly the amygdala. Over the past award period, we have established that baseline EEG measures of anterior asymmetry show good test-retest and internal consistency reliability. Subjects who display accentuated left-sided anterior activation report grater dispositional positive and less negative affect than their right-activated counterparts. Right-activated subjects show decreased natural killer cell activity at baseline and in response to stress. Subjects with increased left-sided prefrontal activation also show faster extinction of a classically conditioned aversive response and more prolonged inhibitor of startle magnitude following a positive stimulus than subjects with less left-sided activation. These findings are consistent with eh notion that prefrontal activity, particularly in the left hemisphere, may inhibit activity in the amygdala, an idea supported in recent animal lesion studies. Finally, we have conducted several studies with acute and remitted depressed subjects where we found that such individuals have decreased activation in the left frontal region. Recently, we have begun a study where regional glucose metabolism with PET along with stimutaneous EEG are recorded in depressed subjects and controls. Our findings to date show that depressives have decreased glucose metabolic activity in a left prefrontal region (area 47). This decrease was inversely correlated with activity in the amygdala and activity in the amygdala in turn was strongly associated with severity of depressive symptoms. Our studies over the next five years will continue these lines of research. We seek to characterize the time course of emotion activation and related individual differences in time course to measures of anterior asymmetry. We will perform a functional magnetic resonance study to examine patterns of prefrontal, anterior temporal and amygdala activation and their inter-relations in response to emotional pictures. We will continue our research using combined electrophysiological and PET measures in depressed patients and controls and follow the depressives through a course of pharmacological and cognitive therapy. This will enable us to determine if the decrease in left prefrontal activation and increase in amygdala activation is state- independent. Finally, using the twin method in infants, we will continue our studies of relations between prefrontal electrophysiological asymmetries and childhood temperament and determine for the first time whether their is a heritable influence and provide an estimate of the strength of this influence. The prior RSDA award has been decisive in facilitating my research career and enabling me to learn new methods and develop several important collaborations. The research proposed offers considerable promise in facilitating our understanding of the mechanisms and causes of affective style and affective disorders.